Certain thiazole-5-carboxylates

ABSTRACT

5-THIAZOL CARBOXYLATES OF THE FORMULA WHEREIN R is an alkali-metal atom, the residue of an organic base or the alkyl radical of an aliphatic, arylaliphatic or alkylheterocyclic alcohol having hypolipemiant activity and their preparation.

United States Patent Clemence et al.

[ 51 Oct. 24, 1972 [54] CERTAIN THIAZOLE-S- CARBOXYLATES [72] Inventors:Francois Clemence, Rosny-sous- Bois; Odile Le Martret, Paris, both ofFrance [73] Assignee: Roussel-UcLaf, Paris, France [22] Filed: July 15,1969 [21] Appl. No.: 842,016

[30] Foreign Application Priority Data [58] Field of Search...260/302 R,294.8, 247.1, 293.68

[56] References Cited OTHER PUBLICATIONS Erlenmeyer et al., Chem.Abstracts, 43:221 (1949). Smith et al., Chem. Abstracts, 19:1706 (1925Wagner et 211., Synthetic Organic Chemistry, N.Y.C., Wiley, 1953, pp.480- 481.

Primary ExaminerAlex Maze] Assistant Examiner-R. J. GallagherAttorney-Hammond & Littell [57] ABSTRACT S-thiazol carboxylates of theformula i I L J-COOR wherein R is an alkali-metal atom, the residue ofan organic base or the alkyl radical of an aliphatic, arylaliphatic oralkylheterocyclic alcohol having hypolipemiant activity and theirpreparation.

8 Claims, No Drawings 1 CERTAIN THlAZOLE-S-CARBOXYLATES OBJECTS OF THEINVENTION provide novel 5- THE INVENTION The novel compounds of theinvention are S-thiazol carboxylates of the formula wherein R is analkali-metal atom, the residue of an organic base or the alkyl radicalof an aliphatic, arylaliphatic or alkylheterocyclic alcohol.

The substituent R is preferably an alkali-metal atom, or the residue ofan organic base such as triethylamine, diisopropylamine, diethylamine,ethanolamine, a collidine, morpholine or piperidine, or the alkylresidue of an aliphatic alcohol containing one to 10 carbon atoms, thealkyl residue of an arylaliphatic alcohol, the aliphatic residue ofwhich contains one to six carbon atoms, the alkyl residue of analkylheterocyclic alcohol, the aliphatic residue of which contains oneto six carbon atoms and the heterocyclic residue of which is the fury]group, thienyl group or pyridyl group.

The compounds of the invention are endowed with interestingpharmacological properties. They possess in particular a remarkablehypolipemiant activity which is manifested by a very significant drop inthe amount of triglycerides. They are devoid of troublesome secondaryeffects, having only a very slight or no vasodilating action.

Preferred compounds of formula I are:

sodium S-thiazol carboxylate,

(3'-pyridyl) methyl S-thiazol carboxylate,

2-p-chlorophenoxy 2-methylpropyl S-thiazol carboxylate,

isopropylidene pyridoxine S-thiazol carboxylate,

N-diethylamino ethyl S-thiazol carboxylate, and its salts of mineral ororganic acids,

2,2'-dimethyl l'-propyl S-thiazol carboxylate.

The novel process of the invention for the preparation of compounds offormula I comprises reacting an alkaline or organic base or an alcoholwith 5-thiazol carboxylic acid or a functional derivative thereof in thepresence of a tertiary amine to fonn the desired salt or ester of 5thiazol carboxylic acid. When 5'-thiazol carboxylic acid is esterifiedby an amino-alcohol, disubstituted on the nitrogen, the resulting estercan be converted into a salt by the action of a mineral or organic acid.

Preferably, the salification of the S-thiazol carboxylic acid iseffected by-means of an alkaline base, for example, an alkali-metalhydroxide or carbonate;

the salificationof the S-thiazol carboxylic acid is effected by means ofw an organic base, for example, triethylamine;

the esterification'of the 5-thiazol carboxylic acid is effected by theaction of a halide of 5-thiazol carboxylic acid on an alcohol, in thepresence of a halogen acid acceptor;

the halogen acid acceptor is a tertiary amine, for example,triethylamine.

The novel hypolipemiant compositions of the invention are comprised ofan effective amount of at least one compound of formula I and a majoramount of a pharmaceutical carrier. The compositions may be in the formof tablets, coated tablets, cachets, capsules, granules, emulsions,syrups and suppositories prepared in the usual manner.

The individual dose is 0.2 g to l g depending upon the method ofadministration.

The hypolipemiant compositions are useful for the treatment of acute orchronic hyperlipemia, atheromatosis, hepatic or toxic steatoses andlipoidic nephroses.

The novel method of the invention of reducing the amount of sanguinelipids in warm-blooded animals comprises administering to warm-bloodedanimals a safe and effective amount of at least one compound of formulaI.

The said compounds may be administered orally or rectally.

The usual useful daily dose is 15 to mg/kg depending upon the method ofadministration.

In the following examples there are described several preferredembodiments to illustrate the invention. However, it should beunderstood that the invention is not intended to be limited to thespecific embodiments.

EXAMPLE I SODIUM S-THIAZOL CARBOXYLATE (R Na) One dissolves 10.25 g. ofS-thiazol carboxylic acid in the stoichiometric quantity of 0.5 Ncaustic soda and evaporates the water under reduced pressure; one thentriturates the residue in alcohol then in ether and dries; one obtainssodium S-thiazol carboxylate with a yield of 97 percent; its meltingpoint is higher than 300 C.

Analysis: C H NO SNa= 151.12

Calculated N percent 9.26

Found 9.12

As far as is known, this compound is not described in the literature.

The starting product, S-thiazol carboxylic acid, is obtained accordingto the process described by H. ER- LENMEYER and H. VON MEYENBURG Helv.Chem. Acta 20, 204, 1937 or H. ERLENMEYER and R. MARBET Helv. Chem. Acta29, 1946-1949, (1 946).

EXAMPLE II (3-PYRIDYL) METHYL S-THIAZOL CARBOXYLATE g. of 3-pyridylmethanol and 23.4 g. of triethylamine in 400 c.c. of ether, whilekeeping the temperature at 20 C; one agitates the reaction mixture for 1hour 30 minutes at ambient temperature, filters, washes the etherealphase with an aqueous solution of potassium carbonate, then with waterand evaporates the solvent under reduced pressure; one obtains(3-pyridyl) methyl S-thiazol carboxylate in the form of colorlesscrystals, which, after recrystallization from isopropyl ether, melt at64 C (Yield 47 percent).

Analysis C H N O S 220.24

Calculated N percent 12.72

Found: 12.73-12.72

As far as is known, this compound is not described in the literature.

'S-Thiazol carboxylic acid chloride is obtained starting with 5-thiazolcarboxylic acid according to the usual methods of chlorination.

(Bambi-G0 One pours a solution of 14.7 g. of S-thiazol carboxylic acidchloride in 90 c.c. of acetone, into a solution of 18.15 g. of2-p-chlorophenoxy 2-methyl 1-propanol and 12.21 g. of triethylamine in50 c.c. of acetone, while keeping the temperature between 20 and 25 C;one agitates for 1 hour at ambient temperature, filters and distills offthe solvent under reduced pressure; one takes up the residue with ether,washes the ethereal solution with an aqueous solution of sodiumcarbonate, then with water; one distills off the etherunder reducedpressure and obtains 2-p-chlorophenoxy 2'-methylpropyl S-thiazolcarboxylate in the form of colorless crystals which, afterrecrystallization from isopropanol, melt at 77 C (Yield 76 percent).

Analysis C l-l ClNO S 31 1.78

Calculated N percent 4.49 Cl percent 1 1.37

Found 4.48-4.50 11.47-11.49

As far asis known, this compound is not described in the literature.

The starting product, 2-p-chlorophenoxy 2-methyl lpropanol, is obtainedin the following way: One adds to a solution of 56.4 g. of ethylpchlorophenoxy isobutyrate in 250 c.c. of ether, a suspension of 8.8 g.of lithium-aluminum hydride in 250 c.c. of ether, while keeping thetemperature between 0 and +5 C; one agitates the reaction mixture for 1hour 30 minutes, at ambient temperature, adds 20 c.c. of water andfilters; the filtrate is washed with water and distilled under reducedpressure; one obtains 39.60 g. of 2-p-chlorophenoxy Z-methyl lpropanol,in the form of a liquid boiling at 99 102 C under 0.3 mm. of mercury(Yield 85 percent), [n] 1.5281.

Analysis O l-1 C 200.65

Calculated Cl percent 17.67

Found: 17.72-17.61

I.R. Spectrum:

LII

' Presence of --()H at 3425 As far as is known, this compound is notdescribed i the literature. 1

EXAMPLE IV lSOPROPYLlDENE PYRIDOXINE 5-THIAZOL CARBOXYLATE M Q One addsto a solution of 5.55 g. of S-thiazol carboxylic acid chloride in 40c.c. of acetone, a solution of 8.11 g. of isopropylidene pyridoxine and4.7 g. of triethylamine in 160 c.c. of acetone, while keeping thetemperature between 20 and 25 C; one agitates for 1 hour 30 minutes atambient temperature, filters and evaporates the solvent under reducedpressure; one takes up the residue with ether, washes the ethereal phasewith an aqueous solution containing 10 percent potassium carbonate, thenwith water and distills off the ether; one obtains isopropylidenepyridoxine 5- thiazol carboxylate in the form of colorless crystalswhich, after recrystallization from ethanol, melt at 132 C (yield 40percent). 7

AnalySiS I C15H16N2O4S Calculated N percent 8.74

Found: 8.67-8.67

As far as is known, this compound is not described in the literature.

I The isopropylidene pyridoxine is obtained according to the processdescribed by W. KORYTNYK and W. WIEDEMAN, J. Chem. Soc. 2531-2532(1962).

EXAMPLE V: N-DIETHYLAMINO ETHYL 5- THIAZOL CARBOXYLATE DIHYDROCHLORIDEOne adds, to 2.77 g. of S-thiazol carboxylic acid chloride, 40 c.c. ofdiethylamino ethanol while cooling; then one heats the mixture to C forhalf-an-hour and distills off the excess diethylamino ethanol underreduced pressure; one takes up the residue with 5 0 c.c. of ethanol andadds 2.87 g. of triethanolamine; one filters, distills the residual oiland collects the fraction boiling between 101 and 154 C under 10 mm. ofmercury; one obtains diethylamino ethyl S-thiazol carboxylate with ayield of 49 percent.

By treating this base with the stoichiometric quantity of hydrochloricacid in ethanol, one obtains diethylamino ethyl S-thiazol carboxylatedihydrochloride in the form of colorless crystals which, afterrecrystallization from ethanol, melt at 116 C (Yield: 45.5 percent).

Analysis C H N O S,2 HCl 301.23

Calculated N percent 9.30 Cl percent 23.64 Found 9.21 23.3-23.4

(IR-:CHzCHaN EXAMPLE VI 2 2,2-D1METHYL 1'-PROPYL THIAZOL CARBOXYLATE(R=CH:- CH;

One slowly adds a solution of 5.5 g. of S-thiazol carboxylic acidchloride in 20 c.c. of acetone to a solution of 3.10 g. of neopentylalcohol and 4.73 g. of triethylamine in 20 c.c. of acetone; one filters,evaporates the solvent under reduced pressure and takes up the residuewith ether; one washes the ethereal solution with an aqueous solution ofpercent potassium carbonate, then with water; one drives off the etherand distills off the residual oil; one collects the fraction passingfrom 1 30 to l 32 C under a pressure of mm. of mercury and obtains2',2'-dimethyl 1'-propyl 5- thiazol carboxylate, with a yield of 35.5percent, in the form ofa liquid, [n] 1.4929-1 .4928.

Analysis C H NO S= 199.26

Calculated N percent 7.03

Found 7.22

As far as is known, this compound is not described in the literature.

PHARMACOLOGICAL DATA A Determination of l-lypolipemiant Activity Thehypolipemiant activity was determined on rats TABLE I Amounts of Dosesadmitriglycerides nistered in mg cc reduction Control 0 33.4 2'-p-chlorophenoxy 20 mg/kg 15.0 55 2'-methylpropyl- 40 mg/kg l6.4 -5lS-thiazol 80 mg/kg 17.7 47 carboxylate l60 mglkg l2.4 -63 Table 1 showsthat the studied compound shows an important hypolipemiant activity evenat a dose of 20 B. Determination of Acute Toxicity The acute toxicitywas determined on male mice weighing about 20 gm. The product understudy was administered as an aqueous suspension either byintraperitoneal route or orally.

The lethal dose, ID of 2-p-chlorophenoxy 2'- methyl propyl S-thiazolcarboxylate, which was. determined according to the method of Miller etal., was 0.90 mg/kg by intraperitoneal route and more than 2 g/kg.orally.

Various modifications of the compoisitions and method of the inventionmay be made without departing from the spirit or scope thereof.

. We claim:

ltA5rtb aq sellzafi e Q8199 iqr a.

--COOR wherein R is selected from the group consisting of an alkalimetal atom, triethylamino, diisopropylamino, diethylamino, ethanolamino,collidino, morpholino, piperidino and phenyl alkyls and chlorophenoxyalkyls with one to six alkyl carbon atoms and heterocyclic alkyls of oneto six carbon atoms, said heterocyclic being selected from the groupconsisting of fury], thienyl and pyridyl.

2. A compound of claim 1 which is sodium S-thiazol carboxylate.

3. A compound of claim 1 which is (3-pyridyl) methyl S-thiazolcarboxylate.

4. A compound of claim 1 which is 2'-pchlorophenoxy 2'-methylpropylS-thiazol carboxylate.

' 5. A compound of claim 1 which is isopropylidene pyridoxine S-thiazolcarboxylate.

6. N-diethylamino-ethyl S-thiazolcarboxylate and its non-toxic,pharrnaceutically acceptable acid addition salts.

7. A compound of claim 1 which is the dihydrochloride ofN-diethylaminoethyl S-thiazolcarboxylate.

2. A compound of claim 1 which is sodium 5-thiazol carboxylate.
 3. Acompound of claim 1 which is (3''-pyridyl) methyl 5-thiazol carboxylate.4. A compound of claim 1 which is 2''-p-chlorophenoxy 2''-methylpropyl5-thiazol carboxylate.
 5. A compound of claim 1 which is isopropylidenepyridoxine 5-thiazol carboxylate.
 6. N-diethylamino-ethyl5-thiazolcarboxylate and its non-toxic, pharmaceutically acceptable acidaddition salts.
 7. A compound of claim 1 which is the dihydrochloride ofN-diethylaminoethyl 5-thiazolcarboxylate.
 8. 2'',2''-dimethyl 1''-propyl5-thiazol carboxylate.